The Switch from Fetal to Adult Hemoglobin

Abstract

The fetal-to-adult hemoglobin switch and silencing of fetal hemoglobin (HbF) have been areas of long-standing interest among hematologists, given the fact that clinical induction of HbF production holds tremendous promise to ameliorate the clinical symptoms of sickle cell disease (SCD) and b-thalassemia. In this article, we discuss historic attempts to induce HbF that have resulted in some therapeutic approaches to manage SCD and b-thalassemia. We then go on to discuss how more recent molecular studies that have identified regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction. We go on to discuss strategies by which such approaches may be developed. Older studies in this field can provide important lessons for future studies aimed at developing more effective strategies for HbF induction, and we therefore chronologically cover the work accomplished as this field has evolved over the course of the past four decades.A s with many facets of the history of the hemoglobin field, the study of the fetal-toadult hemoglobin switch and work on fetal hemoglobin silencing has a rich and storied history that spans the course of several decades. In this work, we begin with a historic overview of this field and then move on to discuss more recent molecular findings that are providing important new insight into this process. There is great hope that these new molecular studies may lead to important targeted therapeutic advances for fetal hemoglobin (HbF) induction. However, the historic work in this field suggests that the road to effective therapies may not always be straightforward and reconsidering seemingly simple observations can often yield important new insights. There are many valuable lessons that can be learned from both the historic and more recent work in this field and therefore we attempt to cover the chronology of findings that have resulted in our current understanding of the fetal-to-adult hemoglobin switch.The disorders of b-hemoglobin, sickle cell disease (SCD) and b-thalassemia, are major sources of morbidity and mortality worldwide (Weatherall et al. 2006). These diseases are the

Establishing a hematopoietic genetic network through locus-specific integration of chromatin regulators

“…1E). SetD8 knockdown did not alter expression of the established repressor of embryonic/ fetal β-like globin genes Bcl11a, or Klf1, which can induce BCL11A expression (43) (Fig. 1E).…”

IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts

“…In the context of fetal hemoglobin regulation, the effects of IGF2BP1-OE upon five erythroid-related transcription factors (BCL11A, HMGA2, ZBTB7A, KLF1, and SOX6) were investigated (27)(28)(29). IGF2BP1-OE caused little change in the mRNA levels of these genes with the exception of a small, but statistically significant decrease in ZBTB7A (Fig.…”

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…While these disorders have been considered to be simple monogenic disorders with recessive inheritance, clinical observations have highlighted the substantial phenotypic diversity in these cases (30). Indeed, there are some individuals harboring disease-causing mutations who are entirely asymptomatic.…”

“…In both sickle cell disease and β-thalassemia, elevated levels of fetal hemoglobin (HbF), a form of hemoglobin predominantly expressed throughout gestation that normally gets silenced shortly after birth, have been shown to ameliorate clinical symptoms in a quantitative manner. To address this heterogeneity in HbF expression and clinical severity in hemoglobin disorders, we and others utilized genome-wide association studies (GWAS) several years ago in both nonanemic and sickle cell disease populations to identify common genetic variants associated with HbF levels (30)(31)(32)(33). GWAS allow one to assess whether any one of thousands to millions of common genetic variants are associated with a particular trait or disease of interest (34).…”